The present invention is directed to the development of an antiserum and assay which reflects the in vivo activity of stromelysin in certain animal models as well as in those disease states where stromelysin is thought to play a major and/or central role. In addition, this antiserum and assay allow the evaluation of specific and selective inhibitors of stromelysin in these various diseases. Over 32 million Americans have some type of musculoskeletal disease, and of these, half have osteoarthritis (OA). OA is significantly more prevalent than rheumatoid arthritis (RA). In both RA and OA, there is degradation and loss of cartilage aggrecan and collagen which ultimately results in degradation of the underlying bone. Although the end result is similar for these two diseases, the mechanisms by which these diseases begin and progress appear to be different. RA is an inflammatory disease in which various cytokines such as IL-1 and TNF.alpha. have been implicated to stimulate the synovium to proliferate and produce degradative enzymes. On the other hand, OA is a disease which seems to develop from within the cartilage, in which biochemical and biomechanical factors play a major role. For instance, patients with cruciate ligament and meniscal injuries, which destabilize the joint, tend to develop OA at an accelerated rate. In OA, there appears to be synthesis of degradative proteinases by the chondrocytes with synovial hypertrophy and inflammation occuring late in the disease. The degradative proteinase stromelysin (SLN) is common to both OA and RA and may be responsible for the cartilage connective tissue destruction observed in both of these diseases.
SLN is synthesized by chondrocytes and synoviocytes and its synthesis is upregulated by inflammatory cytokines both in vitro and in vivo. Its expression is elevated in animal models of arthritis and in patients with OA, RA and traumatic joint injury. SLN has the capacity to degrade the major cartilage connective tissue elements, including aggrecan, link protein, and type IX collagen. Aggrecan is a large anionic proteoglycan which is responsible for maintaining cartilage's resistance to compression. It is one of the first molecules to be lost from OA cartilage. The release of this molecule appears to be required prior to collagenolytic degradation of type II collagen. 72 kDa and 95 kDa gelatinases are two other members of the metalloproteinase family which have the capacity to degrade aggrecan. However, the expression of the 72 kDa enzyme is not upregulated in either OA or RA. Also, SLN may participate in the activation of both collagenase (CLN) and 95 kDa gelatinase (GEL). Therefore, by inhibiting SLN, we may be able to inhibit and slow the rate of degradation, either directly or indirectly, of all of the major cartilage macromolecules in OA. Presently, general immunological [Heinegard et al., (1985), Scand. J. Clin. Lab Invest., 45, pp. 421-427; Caterson etal., Monoclonal Antibodies Against Cartilage Proteoglycan And Link Protein; in: Articular Cartilage Biochemistry, eds. K.E. Keuttner, R. Schleyerbach and V.C. Hascall, Raven Press, N.Y., 1986, pp. 59-73] and dye based [Farndale et al., (1986), Biochem. Biophys Acta, 882, pp. 173-177] assays are used to quantify aggrecan. These assays do not differentiate degraded from intact aggrecan molecules.